Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis

Kim, Kevin K.; Wei, Ying; Szekeres, Charles; Kugler, Matthias C.; Wolters, Paul J.; Hill, Marla L.; Frank, James A.; Brumwell, Alexis; Wheeler, Sarah E.; Kreidberg, Jordan A.; Chapman, Harold A.

doi:10.1172/jci36940

Cited by 270 publications

(335 citation statements)

References 51 publications

(56 reference statements)

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“…9,10,25,29,32,84e88 In two independent experiments, a substantial population of myofibroblasts reported transgenic expression from an incomplete section of the human surfactant protein C promoter after lung injury. 32,86 Because transcription of endogenous surfactant protein C is specific for type II airway epithelial cells, these results support the epithelial-tomesenchymal transition hypothesis that pathogenic myofibroblasts originate from dedifferentiated epithelial cells. 79 However, a different reporter system inserted into the endogenous mouse Sftpc locus found epithelial cells did not become myofibroblasts in the bleomycin lung injury model.…”

Section: Myofibroblasts In Lung Fibrosis and Degenerationsupporting

confidence: 56%

Lung Pericytes and Resident Fibroblasts

Barron

Gharib

Duffield

2016

The American Journal of Pathology

100

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Pericytes, resident fibroblasts, and mesenchymal stem cells are poorly described cell populations. They have recently been characterized in much greater detail in rodent lungs and have been shown to play important roles in development, homeostasis, response to injury and pathogens, as well as recovery from damage. These closely related mesenchymal cell populations form extensive connections to the lung's internal structure, as well as its internal and external surfaces. They generate and remodel extracellular matrix, coregulate the vasculature, help maintain and restore the epithelium, and act as sentries for the immune system. In this review, we revisit these functions in light of significant advances in characterizing and tracking lung fibroblast populations in rodents. Lineage tracing experiments have mapped the heritage, identified functions that discriminate lung pericytes from resident fibroblasts, identified a subset of mesenchymal stem cells, and shown these populations to be the predominant progenitors of pathological fibroblasts and myofibroblasts in lung diseases. These findings point to the importance of resident lung mesenchymal populations as therapeutic targets in acute lung injury as well as fibrotic and degenerative diseases. Far from being passive and quiescent, pericytes and resident fibroblasts are busily sensing and responding, through diverse mechanisms, to changes in lung health and function. (Am J Pathol 2016 http://dx

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Section: Myofibroblasts In Lung Fibrosis and Degenerationsupporting

confidence: 56%

Lung Pericytes and Resident Fibroblasts

Barron

Gharib

Duffield

2016

The American Journal of Pathology

100

View full text Add to dashboard Cite

show abstract

“…Furthermore, GnT-III expression consistently inhibited β-catenin translocation from cell-cell contact into the cytoplasm and nucleus. GnT-III expression suppressed p-β-catenin/p-Smad2 complex formation, which was essential for initiation of EMT [62,63]. Taken together, these observations clearly demonstrate that GnT-III plays important roles in EMT, and to explain a molecular mechanism for the inhibitory effects of GnT-III on cancer metastasis.…”

Section: A Mutual Regulation Between Gnt-iii Expression and E-cadherimentioning

confidence: 56%

Potential roles of N-glycosylation in cell adhesion

Isaji

et al. 2012

Glycoconj J

126

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The functional units of cell adhesion are typically multiprotein complexes made up of three general classes of proteins; the adhesion receptors, the cell-extracellular matrix (ECM) proteins, and the cytoplasmic plaque/peripheral membrane proteins. The cell adhesion receptors are usually transmembrane glycoproteins (for example E-cadherin and integrin) that mediate binding at the extracellular surface and determine the specificity of cell-cell and cell-ECM recognition. E-cadherin-mediated cell-cell adhesion can be both temporally and spatially regulated during development, and represents a key step in the acquisition of the invasive phenotype for many tumors. On the other hand, integrin-mediated cell-ECM interactions play important roles in cytoskeleton organization and in the transduction of intracellular signals to regulate various processes such as proliferation, differentiation and cell migration. ECM proteins are typically large glycoproteins, including the collagens, fibronectins, laminins, and proteoglycans that assemble into fibrils or other complex macromolecular arrays. The most of these adhesive proteins are glycosylated. Here, we focus mainly on the modification of N-glycans of integrins and laminin-332, and a mutual regulation between cell adhesion and bisected N-glycan expression, to address the important roles of N-glycans in cell adhesion.

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“…12,14 Furthermore, inhibition of EMT by knockout of the integrin-a3 gene has been shown to suppress bleomycininduced pulmonary fibrosis in mice. 15 These results suggest that some of the lung myofibroblasts in pulmonary fibrosis patients originate from lung epithelial cells through the EMT, and that EMT has an important role in the pathogenesis of the condition, including that induced by drugs. However, the involvement of EMT in drug-induced pulmonary fibrosis has not previously been examined.…”

mentioning

confidence: 74%

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

et al. 2010

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Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-b was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.

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Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis

Cited by 270 publications

References 51 publications

Lung Pericytes and Resident Fibroblasts

Lung Pericytes and Resident Fibroblasts

Potential roles of N-glycosylation in cell adhesion

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

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